Chordoma is a rare bone cancer primarily of the spine arising from embryonic remnants of the notochord that is aggressive, locally invasive, and has a poor prognosis (Chugh et al., 2007, The Oncologist 12:1344-1350). It occurs more frequently in men than women (60% vs. 40%), with a median age at diagnosis of 59 years with a generally progressive increase in incidence with age (McMaster et al., 2001, Cancer Causes Control 12: 1-11). Despite being frequently misquoted in the literature as having a proclivity for the sacrococcygeal region, the most comprehensive population analysis of 400 cases from the SEER data base indicate chordomas are almost equally distributed between the sacrum (29.2%), skull base (32%), and mobile spine (32.8%) (McMaster et al., ibid.; Walcott et al. (2012) Lancet Oncol 13:e69-76). In this study, median overall survival was 6.29 years with 5-year, 10-year and 20-year survival dropping precipitously to 68%, 40% and 13% respectively, across all races and sex (McMaster et al., supra). However, it is important to note that the authors identified that patients diagnosed and treated later in the 22-year survey had significantly improved survival, and hypothesized that this was a result of improved surgical and radiation techniques. Four later (smaller) studies support this hypothesis with a total of 230 subjects having 5-year and 10-year overall survival of 82% and 57% (Ferraresi et al. (2010), BMC Cancer 10:22. (Table 4); Stacchiotti et al. (2010), Ann Surg Oncol 17(1):211-9).
The United States incidence of chordoma is 0.08 per 100,000 resulting in approximately 250 new U.S. cases annually (McMaster et al., supra; U.S. Census Bureau estimate of U.S. population (315,091,138) as of Jan. 1, 2013). The incidence in Europe-27 (EU) is similar to the U.S., resulting in approximately 400 new EU cases annually (Chordoma Foundation website, 2013; European Commission EuroStat database EU-27 population as of Jan. 1, 2012 (503,700,000)). With an average overall survival of approximately 10 years, the prevalence of chordoma is approximately 8 per million, or about 2500 in the U.S. and 4000 in EU. The incidence and prevalence of chordoma in other regions is unknown.
Chordomas are indolent and slow growing, therefore they are often clinically silent until later stages of disease. Chordomas are not typically metastatic on presentation, with only 5% showing metastasis to the lungs, bone, skin and brain at the time of initial presentation. Patient survival appears to be less affected by distant metastasis than by local progression of the disease. Local progression has emerged as the most important predictor of mortality, and the extent of initial resection has become the most important factor in affording an opportunity for cure (Walcott et al., supra).
Aggressive surgical resection with an emphasis on neurological preservation, followed by adjuvant radiation therapy is the standard of care for this disease. Aggressive en-bloc surgical resection with wide surgical margins has substantially improved local control of disease recurrence (Hsieh et al. (2009), Spine 34:2233-39; Stacchiotti et al., supra; Tzortzidis et al. (2006), Neurosurgery 59(2):230-7). However, complex removal of the tumor itself is not a satisfactory treatment goal; preservation of a patient's neurological function and quality of life must also take priority when assessing surgical outcomes. Any tumor that remains after surgery, particularly when small in volume, is managed with radiotherapy. Currently, complete resection is attainable in ˜50% of sacral chordomas, with much lower rates for spinal and skull base chordomas (Walcott et al., supra). While stand-alone radiotherapy has proven to be ineffective, there appears to be a consensus that Hadron-based (not photon) adjuvant radiotherapy offers an added advantage over surgery alone, with 5-year local control rates of 50-60% (Walcott et al., supra).
Chordomas are generally insensitive to conventional chemotherapies, as expected given their slow growing nature (Azzarelli et al. (1988), J Surg Oncol 37(3):185-91). However, limited case reports have suggested dedifferentiated chordoma may be sensitive to aggressive chemotherapy (Fleming et al. (1993), Cancer 72:714-18). Molecular profiling of chordomas has revealed these tumors over express PDGF receptors A and B, as well as KIT receptors. As a result, several tyrosine kinase inhibitors such as imatinib and sunitinib have been tried in chordoma patients. The best results obtained to date were with sunitinib where 44% of patients with chordoma (4/9) had stable disease for 16 weeks (Merriam et al. (2009), J Clin Oncol 27: 3154-60).
Accurate diagnosis of spinal and skull based tumors is important. Brachyury has become a discriminating biomarker for chordoma. When combined with cytokeratin staining, sensitivity and specificity for detection of chordomas is 98% and 100% respectively (Oakley et al. (2008), Mod Path 21, 1461-1469). Brachyury, also known as “T”, is a mesodermal transcription factor and member of the T-box complex of genes, playing a role in early development, as well as the formation and differentiation of posterior mesoderm and axial development in vertebrates (see, e.g., Wilkinson et al., 1990, Nature 343(6259):657-659); Beddington et al., 1992, Development (Suppl.):157-165; Schulte-Merker et al., 1994, Development 120: 1009-1015; Kispert and Herrmann, 1994, Dev. Biol. 161:179-193; Showell et al., 2004, Dev Dyn 229:201-218). More recently, Palena and colleagues have demonstrated that Brachyury is expressed in a variety of human tumor tissues and cancer cell lines (Palena et al., 2007, Clin. Cancer Res. 13(8):2471-2478). Studies by Fernando et al. have shown that Brachyury promotes the epithelial-mesenchymal transition (EMT) in human tumor cells, conferring on tumor cells a mesenchymal phenotype, as well as migratory and invasive abilities, while attenuating tumor cell cycle progression (Fernando et al., 2010, J. Clin. Invest. 120(2):533-544). Accordingly, Brachyury is involved in metastatic progression of cancer. However, in chordoma, Brachyury appears to be more broadly involved at all stages of the disease. In patients with familial and sporadic chordoma, studies have identified a common gene duplication of brachyury (Yang et al., Nat Genet 2009; 41: 1176-78).
Despite best efforts at initial treatment, most chordomas will recur or progress. While many patients elect to undergo complex reoperations, despite a high rate of morbidity for all lesion locations, there are very few reports of treatment protocols and outcomes for recurrent lesions. Previous radiation treatment often limits the ability to safely re-irradiate, as well as causing increased morbidity for subsequent surgeries. Accordingly, there is a need in the art for improved therapeutic approaches for the treatment of chordoma. In addition, given the occurrence of familial chordoma, there is a need in the art for options for the prevention of chordoma, or options that delay the onset of, or improve the outcomes in, familial chordoma.